Isoquinoline derivatives for the treatment of glaucoma or ocular hypertension

ABSTRACT

The use of isoquinoline derivatives for the treatment of glaucoma or ocular hypertension. The isoquinoline derivatives are of formula I &lt;IMAGE&gt;  wherein R1 is a hydrogen atom or a C1-C6 alkyl group and R2 is a C1-C6 alkyl group. The stability of the isoquinoline derivatives when used in the form of a solution is improved by incorporating therein compounds having a phenolic hydroxyl group and/or glycols serving as a stabilizer.

This is a division of application Ser. No. 495,386 filed on Mar. 16,1990 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is concerned with the use of isoquinoline derivatives forthe treatment of glaucoma or ocular hypertension. More particularly, theinvention relates to ophthalmological compositions containing an activeamount of these isoquinoline derivatives or the pharmaceuticallyacceptable salts thereof.

2. Description of the Prior Art

Glaucoma is an ocular disorder that causes functional or organicdisturbances in the eyes due to continuous or repeated increase inintraocular pressure. The treatment of glaucoma is required to reduce anintra ocular pressure to the normal level in order to maintain opticfunctions.

Pilocarpine eye drops have been used extensively for the treatment ofglaucoma. It is known however that pilocarpine eye drops not only reducean intraocular pressure but also act on musculi sphincter pupillae andcilia thereby causing side effects such as darkness feeling due tomiosis, conjunctival congestion and accommodative injection. Such sideeffects may invite very serious dangers in operation particularly topersons engaging in transportation. In the case of an elderly patientwith cataract, miosis will result in an increased visual disorder. Theseproblems have encouraged development of drugs for the treatment ofglaucoma to be substituted, for pilocarpine eye drops.

Epinephrine eye drops being a product of such needs are also associatedwith side effects such as conjunctival congestion, pain at the eyebrowand allergic blepharoconjunctivitis. The eye drops sometimes bring aboutincreased intraocular pressure due to mydriasis and are rarely used. Inaddition, drugs such as surface-anesthetic agents, pschotropic agents,etc. have been attempted for clinical use in the treatment of glaucomabut none of them is put in practice.

Recently β-receptor blockers have become promising in this field, andtimolol maleate, carteolol hydrochloride and befunolol hydrochloride arecommercially available as drugs for the treatment of glaucoma.

In view of such situations, we have investigated further medicinal useof isoquinoline derivatives having β-adrenergic blocking activity asdisclosed in Japanese Patent Publications No. 41673/1978 and No.55512/1988 and found that they possess an intraocular pressure reductionactivity and are useful for the treatment of glaucoma and ocularhypertension. As far as we know, it has not been reported that theisoquinoline derivatives as disclosed above have been used for thetreatment of glaucoma or ocular hypertension.

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus relates to a compound of formula I ##STR2##wherein R₁ is a hydrogen atom or a C₁ -C₆ alkyl group and R₂ is a C₁ -C₆alkyl group and the pharmaceutically acceptable salt to be used for thetreatment of glaucoma or ocular hypertension.

In the above formula I, the C₁ -C₆ alkyl group includes preferablystraight or branched alkyl groups of 1-4 carbon atoms, e.g., methyl,ethyl, propyl, isopropyl, butyl and tert.-butyl. The pharmaceuticallyacceptable salts include the salts of the compounds with inorganic ororganic acids such as hydrochloric, sulfuric, nitric hydrobromic,oxalic, maleic, fumaric, citric, tartaric or malic acid.

Representative examples of the compounds of formula I are illustratedbelow.

4-(3-tert.-Butylamino-2-hydroxypropoxy)-1-isoquinolinone,

4-(3-tert.-butylamino-2-hydroxypropoxy)-2-methyl-1-isoquinolinone,

4-(3-Isopropylamino-2-hydroxypropoxy)-1-isoquinolinone,

4-(3-Isopropylamino-2-hydroxypropoxy)-2-methyl-lisoquinolinone,

4-(3-Ethylamino-2-hydroxypropoxy)-1-isoquinolinone,

4-(3-Ethylamino-2-hydroxypropoxy)-2-methyl-lisoquinolinone and

4-(3-Ethylamino-2-hydroxypropoxy)-2-ethyl-lisoquinolinone.

Further, the invention relates to compositions for the treatment ofglaucoma or ocular klypertension which comprises as an active ingredientan effective intraocular pressure reducing amount of a compound offormula I ##STR3## wherein R₁ is a hydrogen atom or a C₁ -C₆ alkyl groupand R₂ is a C₁ -C₆ alkyl group and the pharmaceutically acceptable salt.Preferred concentration of the active ingredient in the composition isusually in the range of about 0.1 to 5% by weight.

The compositions of the invention are prepared in unit dosage form byblending the compounds of formula I or the pharmaceutically acceptablesalts thereof with an ophthalmologically compatible carrier. As the unitdosage form may be employed any of various forms as needed such as eyeointments, eye drops-for topical administration, and tablets, granules,injections for systemic administration. The mode of use in the form ofeye drops is preferred in terms of such effects as rapid onset, easinessin administration and smaller dose.

The compositions of the invention are preferably administered at a dailydose for the active ingredient in adults usually between 0.005 and 2.5mg and more preferably between 0.025 and 1.0 mg divided in one toseveral doses, although the dosage is not particularly limited.

The dosage forms in the present invention can be prepared by blendingthe active ingredients with ophthalmologically compatible carriers andif required shaping the blend. In cases where the dosage form is in sucha form as eye ointments, eye drops or injections, further sterilizationtreatment is required. The carriers may appropriately be selecteddepending upon the dosage forms. In preparing the eye ointments,conventional carriers such as emulsifiable, water-soluble or suspensiblecarriers may be employed. They include e.g., white petrolatum,plastibase 50 W, purified lanolin and liquid paraffin. In preparing theeye drops, sterilized distilled water may be used as a carrier.

In the preparation of the dosage forms, ophthalmologically compatibleadditives may be further employed which include a solubilizing adjuvant,a stabilizing aid, a viscosity increasing agent, a buffer, anantioxidant, a preservative and the like. The solubilizing adjuvants mayinclude sodium carboxymethyl cellulose, polyoxyethylene glycol etherssuch as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether,polyethylene glycol higher fatty acid esters such as polyethylene glycolmonolaurate and polyethylene glycol monooleate and polyoxyethylene fattyacid esters such as polyoxyethylene sorbitan monolaurate andpolyoxyethylene sorbitan monooleate.

The stabilizing aid may include, sodium benzoate, ethanol, benzylalcohol, D-mannitol, glucose or the like. The viscosity increasingagents may include methyl cellulose, liydroxypropylmethyl cellulose,polyvinyl alcohol, carboxymethyl cellulose, hydroxyethyl cellulose,polyvinyl pyrrolidone, glycerin, carboxyvinyl polymers or the like. Thebuffers may include sodium dihydrogen phosphate, sodium monohydrogenphosphate, potassium hydrogen phosphate, boric acid, sodium borate,citric acid, sodium citrate, tartaric acid, sodium tartarate and sodiumacetate. The antioxidants may include sodium bisulfite, sodium sulfite,sodium thiosulfite, sodium pyrosulfite, oxyquinoline sulfate andascorbic acid. The preservatives may include chlorobutanol, benzethoniumchloride, benzalkonium chloride, cetylpyridinium chloride, thimerosaland phenethyl alcohol.

When the compositions of the invention is in the form of eye drops, itis preferable to prepare eye drops that are isotonic to tears, for whichan isotoning agent such as sodium chloride may be added, if required.The eye drops are desirably adjusted to a pH of 5.5 to 9.0, preferably6.5 to 8.5.

Furthermore, we have found that stability of the above compositions whenused in the form of a solution is much improved by incorporating thereinat least one of a compound containing a phenolic hydroxyl group andglycols serving as a stabilizer. The present invention thus relates tostabilized compositions for the treatment of glaucoma or ocularhypertension which comprises an effective intraocular pressure reducingamount of a compound of formula I ##STR4## wherein R₁ is a hydrogen atomor a C₁ -C₆ alkyl group and R₂ is a C₁ -C₆ alkyl group or thepharmaceutically acceptable salt and at least one of a compound offormula II ##STR5## wherein R₃, R₄ and R₅ may be the same or differentand each is a hydrogen atom, a halogen atom, a C₁ -C₆ alkyl group, a C₁-C₆ alkoxy group, a carboxyl group or a C₁ -C₆ alkoxycarbonyl group anda compound of formula III

    HO--[(CH.sub.2).sub.m --O].sub.n --H

wherein m is an integer of 2 to 4 and n is an integer of 1 to 30.

In the above formula II, the halogen atom includes F, Cl, Br and I, theC₁ -C₆ alkyl group includes preferably straight chain or branched alkylof 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyland tert.-butyl, the C₁ -C₆ alkoxy groups include preferably straightchain or branched alkoxy groups of 1 to 4 carbon atoms sucti asmethoxy-, ethoxy, propoxy, isopropoxy, butoxy and tert.-butoxy and theC₁ -C₆ alkoxycarbonyl groups include straight-chain or branchedalkoxycarbonyl groups in which the alkyl moiety contains preferably 1 to4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonylisopropoxycarbonyl, butoxycarbonyl and tert.-butoxycarbonyl.

Representative examples of the compounds of formula II include phenol,o-, m- and p-cresols, methoxyphenol, hydroxybenzoic acid, methylhydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate,isopropyl hydroxybenzoate, butyl hydroxybenzoate, isobutylhydroxybenzoate, butylhydroxyanisol, butylhydroxytoluene,4-chloro-m-cresol and the like.

Examples of the compounds represented by formula (III) include ethyleneglycol, propylene glycol, butylene glycol, polyethylene glycol,polypropylene glycol or the like.

The compounds of formulae II and III as the stabilizer are used eitheralone or in combination therewith and they can be used in an amount upto the maximum of the solubility in the carrier, usually an amount inthe range of 0.02 to 10.00% (w/v) being preferred.

The above stabilized compositions of the present invention areespecially advantageous to the use as eye drops, since they exhibitextended storage stability.. They can be prepared into a variety ofdosage forms in a similar way as described above.

The invention moreover relates to a method for treating glaucoma orocular hypertension. The method consists in contacting a composition ora stabilized composition as described above with the eye in order toreduce eye pressure and to maintain said pressure on a reduced level.The composition contains about 0.1 to 5% by weight of the activesubstance, i.e., the compound of formula I. The treatment mayadvantageously be carried out in that one drop of the composition,corresponding to 0.005-2.5 mg, preferably 0.025-1.0 mg/day for adult maybe administered about 1 to 4 times to the patient's eye.

The compositions of the present invention are administered by a varietyof routes of administration depending on the unit dosage form. Forexample, the eye drops are either dropped into the eyes from anappropriate eye dropper or sprayed onto the eye by means of an atomizer.The eye ointments are applied to the eye. The tablets, granules or thelike is orally administered, and the injections are administeredsubcutaneously, intramuscally or intravenously. The expected therapeuticeffects can equally be produced by any of the mentioned routes.

The invention is illustrated by means of the following non-limitativeexamples.

EXAMPLE 1

    ______________________________________                                        4-(3-tert-Butylamino-2-hydroxypropoxy)-2-                                                             10      mg                                            methyl-1-isoquinolinone hydrochloride                                         Benzethonium chloride   0.1     mg                                            Sodium chloride         3       mg                                            Sodium dihydrogen phosphate                                                                           5       mg                                            Sodium monohydrogen phosphate.12H.sub.2 O                                                             11.8    mg                                            Distilled water         q.s.                                                  Total                   1       ml                                            ______________________________________                                    

A solution of the above-mentioned components in distilled water wassubjected to sterile filtration using a suitable filter to prepare eyedrops.

EXAMPLE 2

    ______________________________________                                        4-(3-tert-Butylamino-2-hydroxypropoxy)-1-                                                             20      mg                                            isoquinolinone hydrochloride                                                  Benzethonium chloride   0.1     mg                                            Sodium chloride         3       mg                                            Sodium dihydrogen phosphate                                                                           5       mg                                            Sodium monohydrogen phosphate.12H.sub.2 O                                                             11.8    mg                                            Distilled water         q.s.                                                  Total                   1       ml                                            ______________________________________                                    

A solution of the above-mentioned components in distilled water wassubjected to sterile filtration using a suitable filter to prepare eyedrops.

Efficacy test

Action of the eye drops produced in the above examples on normalintraocular pressure was investigated in male Japanese white rabbitseach weighing 2.2-2.9 kg. Intraocular pressure was measured by means ofAlcon's pneumatic applanation tonometer (Nippon Alcon Co., Ltd.).

One eye was applied with 100 μl of the drug solution, and changes of theintraocular pressure were measured at time intervals. The intraocularpressure one hour prior to the eye drop application was taken as thepreapplication level. A solution with the active agent excluded from theformulation was used as a control. The control and the formulation wereevaluated in one and the same rabbit at an off-drug period of one week.The results are shown in Tables 1 and 2 below.

                  TABLE 1                                                         ______________________________________                                                 Intraocular pressure (mmHg)                                          No.        Pre-                                                               of         appli-                                                             animals    cation  1 hr.  2    3    4    5    6                               ______________________________________                                        Control                                                                              3       17.8    19.0 17.8 18.0 17.8 19.9 20.7                          Example                                                                              3       19.8    16.0 16.8 15.7 17.2 16.8 18.2                          ______________________________________                                         (Mean value for 3 animals)                                               

                  TABLE 2                                                         ______________________________________                                                 Intraocular pressure (mmHg)                                          No.        Pre-                                                               of         appli-                                                             animals    cation  1 hr.  2    3    4    5    6                               ______________________________________                                        Control                                                                              3       18.9    19.2 18.0 17.6 18.5 17.8 19.0                          Example                                                                              3       19.1    15.2 16.0 16.6 17.3 18.1 17.9                          ______________________________________                                         (Mean value for 3 animals)                                               

The results indicate that the eye drops of the invention can achieveremarkable pressure reduction. Acute toxicity test

4-(3-tert.-butylamino-2-hydroxypropoxy)-2-methyl-1-isoquinolinonehydrochloride and 4-(3-tert.-butylamino-2-hydroxypropoxy)-1-isoquinonehydrochloride, respectively were administered to mice to determine theLD₅₀ value. The results are shown in Tables 3 and 4 below.

                  TABLE 3                                                         ______________________________________                                        Route of                                                                      administration Sex     LD.sub.50 (mg/kg)                                      ______________________________________                                        Oral           Male    1393                                                                  Female  1290                                                   Intraperitoneal                                                                              Male     578                                                                  Female   557                                                   ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Route of                                                                      administration Sex     LD.sub.50 (mg/kg)                                      ______________________________________                                        Oral           Male    2810                                                                  Female  2470                                                   Intraperitoneal                                                                              Male     382                                                                  Female   367                                                   ______________________________________                                    

EXAMPLE 3

In an appropriate amount of a 0.2M solution of disodium hydrogenphosphate were dissolved 1.0 g of4-(3-tert.-butylamino-2-hydroxypropoxy)-2-methyl-l-isoquinolinonehydrochloride (called hereafter "tilisolol hydrochloride") as an activeingredient and 0.1 g of phenol as a stabilizer. A 0.2M solution ofsodium dihydrogen phosphate was added as a buffer so as to adjust pH to7.4, giving a total amount of 100 ml. The resulting solution was sterilefiltered through an appropriate filter paper and divided with 5 mlportions into PET vessels for eye dropping. After stored under lightshielding in a thermostat at 50° C. for 60 days the solution wasanalyzed by HPLC for percent of tilisolol hydrochloride retained. Degreeof coloration was also examined. Stability of the eye drops was comparedwith reference to the percent of tilisolol hydrochloride retained andthe degree of coloration.

EXAMPLES 4-21

The same procedures as in Example 3 were followed except that one or twovarious stabilizers were used in place of phenol used in Example 3. Thecontent of tilisolol hydrochloride was also changed in Examples 16 and17.

EXAMPLES 22-24

The same procedures as in Example 3 were, followed except that one ortwo various stabilizers were used in place of phenol used in Example 3,and the stabilizer was dissolved in an appropriate amount of a 0.05Msolution of sodium borate (in place of the 0.2M solution of sodiumhydrogen phosphate as a buffer) followed by addition of a 0.2M solutionof boric acid so as to adilist pH to 7.4 thus giving a total amount of100 ml.

CONTROL EXAMPLE 1

The same procedure as in Example 3 was followed after preparing asolution of 1.0 g of tilisolol hydrochloride dissolved in distilledwater to a total amount of 100 ml. pH was 5.8 at this time.

CONTROL EXAMPLE 2

The same procedure as in Example 3 was followed except that no phenolwas contained.

CONTROL EXAMPLE 3

The same procedure as in Example 22 was followed except that nostabilizer was contained.

CONTROL EXAMPLE 4

The same procedure as in Example 16 was followed except that nostabilizer was contained.

CONTROL EXAMPLE 5

The same procedure as in Example 17 was followed except that nostabilizer was contained.

Formulae of the solutions prepared in the above Examples and ControlExamples are summarized in Table 5 below.

                  TABLE 5                                                         ______________________________________                                        Tilisolol                                                                     hydro-                                                                        chloride (g) Buffer*  Stabilizer (g)                                          ______________________________________                                        Ex. No.                                                                        3     1.0       P + P    Phenol        0.1                                    4     "         "        o-Methoxyphenol                                                                             0.12                                   5     "         "        m-Methoxyphenol                                                                             0.12                                   6     "         "        p-Methoxyphenol                                                                             0.12                                   7     "         "        o-Hydroxybenzoic acid                                                                       0.14                                   8     "         "        m-Hydroxybenzoic acid                                                                       0.14                                   9     "         "        p-Hydroxybenzoic acid                                                                       0.14                                  10     "         "        Methyl        0.15                                                            m-hydroxybenzoate                                   11     "         "        Methyl        0.15                                                            p-hydroxybenzoate                                   12     "         "        Methyl        0.05                                                            p-hydroxybenzoate                                   13     "         "        Methyl        0.10                                                            p-hydroxybenzoate                                   14     "         "        Methyl        0.20                                                            p-hydroxybenzoate                                   15     "         "        Methyl        0.25                                                            p-hydroxybenzoate                                   16     0.5       "        Methyl        0.15                                                            p-hydroxybenzoate                                                             Propyl        0.05                                                            p-hydroxybenzoate                                   17     2.0       "        Methyl        0.15                                                            p-hydroxybenzoate                                                             Propyl        0.05                                                            p-hydroxybenzoate                                   18     1.0       "        Methyl        0.15                                                            p-hydroxybenzoate                                                             Propyl        0.05                                                            p-hydroxybenzoate                                   19     "         "        4-Chloro-m-cresol                                                                           0.14                                  20     "         "        Propylene glycol                                                                            5.0                                   21     "         "        Methyl        0.02                                                            p-hydroxybenzoate                                                             Ethylene glycol                                                                             5.0                                   22     "         B + B    Ethyl         0.14                                                            p-hydroxybenzoate                                   23     "         "        Propyl        0.14                                                            p-hydroxybenzoate                                   24     1.0       B + B    Methyl        0.26                                                            p-hydroxybenzoate                                                             Ethyl         0.02                                                            p-hydroxybenzoate                                   Control                                                                       Example                                                                        1     1.0       Distilled                                                                              None                                                                 water                                                         2     1.0       P + P    None                                                 3     1.0       B + B    None                                                 4     0.5       P + P    None                                                 5     2.0       "        None                                                ______________________________________                                         *P + P: Prepared by dissolving the stabilizer in a 0.2M solution of           disodium hydrogen phosphate followed by addition of a 0.2M solution of        sodium dihydrogen phosphate to adjust pH to 7.4.                              B + B: Prepared by dissolving the stabilizer in a 0.05M solution of sodiu     borate followed by addition of a 0.2M solution of boric acid to adjust pH     to 7.4.                                                                  

Each of the solutions prepared in the above Examples and ControlExamples was tested for percent of tilisolol hydrochloride retained anddegree of coloration. The results are shown in Table 6 below.

                  TABLE 6                                                         ______________________________________                                        Stability of tilisolol hydrochloride                                          in a thermostat at 50° C. after 60 days                                        Percent of tilisolol                                                                          Degree of                                                     hydrochloride retained (%)                                                                    coloration                                            ______________________________________                                        Example                                                                       No.                                                                            3        84.85             +                                                  4        76.29             ++                                                 5        95.92             +                                                  6        99.00             +                                                  7        81.82             ++                                                 8        96.97             +                                                  9        100.00            +                                                 10        102.92            -                                                 11        106.12            -                                                 12        84.16             +                                                 13        97.96             +                                                 14        105.10            -                                                 15        106.12            -                                                 16        107.27            -                                                 17        95.05             +                                                 18        102.02            -                                                 19        81.63             +                                                 20        101.05            -                                                 21        103.06            -                                                 22        91.74             -                                                 23        79.38             +                                                 24        93.33             -                                                 Control                                                                       Example                                                                        1        0.00              ++++                                               2        53.06             +++                                                3        0.00              ++++                                               4        53.33             +++                                                5        32.94             +++                                               ______________________________________                                         ++++: Markedly colored                                                        +++: Considerably colored                                                     ++: Fairly colored                                                            +: Slightly colored                                                           -: Not colored                                                           

The above results indicate that the eye drops of the invention are muchimproved in stability as compared with those in the Control Examples.

Efficacy test

Action of the eye drops (produced in the above Examples and stored for60 days in a thermostat at 50° C.) on intraocular pressure increasecaused by loading with water or glucose was investigated in maleJapanese white rabbits each weighing 2.2-3.8 kg. Intraocular pressurewas measured by means of Alcon's pneumatic applanation tonometer (NipponAlcon Co., Ltd.).

Action on intraocular pressure increase caused by loading with water

To an eye was applied 100 pl of the eye drops of Example 18. Thirtyminutes later tap water warmed to 37° C. was orally administered bymeans of a rubber catheter at a dose of 50 ml per kg body weight.Intraocular pressure changes after administration of the water weremeasured at time intervals.

For Control Example 6, the same measurements were made using a solutionin which tilisolol hydrochloride was omitted from the solution ofExample 18. Control Example 6 and Example 18 were evaluated in the samerabbits after an off-drug period of one week. The results are shown inTable 7 below.

Action on intraocular pressure increase caused by loading with glucose

To an eye wa-s applied 100 pl of the eye drops of Example 20. Fiftyminutes later a 5% glucose solution was administered via the auriclevein within 60 sec. at a dose of 15 ml per kg body weight. Intraocularpressure changes were measured at time intervals after administration ofthe glucose solution.

For Control Example 7, the same measurements were made using a solutionin which tilisolol hydrochloride was omitted from the solution ofExample 20. Control Example 7 and Example 20 were evaluated in the samerabbits after an off-drug period of one week. The results are shown inTable 8 below.

                  TABLE 7                                                         ______________________________________                                        No. of      Intraocular pressure change (mmHg)                                animals     10      20      30    60    180 min.                              ______________________________________                                        Control 3       5.9     8.6   8.5   1.1   -1.3                                Example 6                                                                     Example 18                                                                            3       1.4     5.0   4.6                                             1.1     -1.6                                                                  ______________________________________                                         (Mean value for 3 animals)                                               

                  TABLE 8                                                         ______________________________________                                        No. of      Intraocular pressure change (mmHg)                                animals     10      20      30    60    180 min.                              ______________________________________                                        Control 3       6.9     4.3   3.8   1.3   -0.7                                Example 7                                                                     Example 20                                                                            3       0       -2.0  -1.6  -4.1  -4.9                                ______________________________________                                         (Mean value for 3 animals)                                               

The above results indicate that the eye drops of the present inventioncould significantly inhibit the intraocular pressure increase.

EXAMPLE 25

1.0 g of tilisolol hydrochloride and 0.02 g of ethyl p-hydroxybenzoatewere dissolved in 0.5 g of a purified water and 2 g of propylene glycol,to which were added 10 g of a purified lanolill. Plastibase 50 W wasadded to the well blended mixture so as to give a total weight of 100 g.The mixture was filled into a tube to prepare an eye ointment.

EXAMPLES 26-29

The viscosity increasing agents shown in Table 9 below were respectivelyadded to the solution prepared in Example 18 in the indicated amount per100 ml of the solution to prepare the eye drops. The eye drops werestored under light shielding in a thermostat at 50° C. for 60 days andevaluated for stability with regard to the percent of tilisololhydrochloride retained and the degree of coloration. The results areshown in Table 9 below.

                  TABLE 9                                                         ______________________________________                                             Viscosity increasing                                                                          Percent of tilisolol                                                                        Degree                                     Ex.  agent (gram per 100                                                                           hydrochloride of                                         No.  ml of the solution)                                                                           retained (%)  coloration                                 ______________________________________                                        26   Hydroxypropylmethyl                                                                           104.3         --                                              cellulose (0.5 g)                                                        27   Polyvinyl pyrrolidone                                                                         107.1         --                                              (0.3 g)                                                                  28   Carboxyvinyl polymer                                                                          102.6         --                                              (0.075 g)                                                                29   Methyl cellulose (1.0 g)                                                                      100.4         --                                         ______________________________________                                    

Further, the effect of the viscosity increasing agent added wasevaluated with regard to the eye drop prepared in Example 18 and thatprepared in Example 26. Each of the eye drops was applied twice with 2541 portions at intervals of 10 sec. to male Japanese white rabbits eachweighing about 3 kg. 25, 60 and 120 minutes after eye dropping, air wasinjected into the rabbits through ear vein. About 0.3 ml of aqueoushumor was taken from the killed rabbits by means of the injector. Theconcentration of tilisolol in the aqueous humor was determined by HPLC.The results are shown in Table 10 below.

                  TABLE 10                                                        ______________________________________                                                Concentration of tilisolol                                                    in aqueous humor (μg/ml)                                                   0   25 min      60 min    120 min                                     ______________________________________                                        Eye drop of                                                                             0     1.15 ± 0.03                                                                            1.30 ± 0.02                                                                        0.92 ± 0.16                            Example 18                                                                    Eye drop of                                                                             0     2.25 ± 0.27                                                                            2.07 ± 0.23                                                                        1.08 ± 0.26                            Example 26                                                                    ______________________________________                                         (Mean value for 3 animals)                                               

What is claimed is:
 1. A method for the treatment of glaucoma or ocularhypertension by contacting the eye with a composition containing aneffective introcular pressure reducing amount of a compound of formula I##STR6## wherein R₁ is a hydrogen atom or a C₁ -C₆ alkyl group and R₂ isa C₁ -C₆ alkyl group and the pharmaceutically acceptable salt and anophthalmologically compatible carrier.